Cigarette smoke-related lung diseases remain one of the most significant contributors to the shortening of life span and illness among our veterans. Over the past decade, our research has identified some of the critical mediators of inflammation that promotes the pathophysiology of human emphysema. Our initial discovery of activated T and B cells in the lungs of former smokers with emphysema, provided the rationale for pursing the role of acquired immunity that can perpetuate inflammation in the lungs of susceptible smokers. Despite smoking cessation, we and others have identified autoreactive CD4 T helper 1 (Th1), and Th17 cells that secrete IFN-? and IL-17A directed against lung matrix proteins in smokers with emphysema. In a pre-clinical model of smoke-induced emphysema, we have shown that smoke activates lung myeloid dendritic cells (mDC) and decreases peripheral immune tolerance, in part by activating complement protein 3 (C3). Among the earliest pathological immune events activated by smoking, accumulation of smoke-derived, particulate matter activates the IL-1?-mediated inflammasome pathways, inhibits anti-inflammatory mediators (e.g., PPAR-?), and expands lung Th1 and Th17 cells. IL-17A and chemokines induced by IFN-? (e.g., CXCL10) strongly upregulate matrix metalloproteinase 12 (MMP12) and MMP9 in mDC, which destroy elastin fibrils in the lungs. Mice exposed to cigarette smoke have activated lung mDCs, which stimulate Th1/Th17 cell differentiation and are critical in emphysema development. However, the molecular mechanisms responsible for smoke-mediated activation of mDCs, and the downstream pathways that promote emphysema development remain unknown. Our microarray analysis of human lung mDCs showed significantly reduced expression of complement protein 1 (C1q) mRNA in emphysema, and acquired loss of C1q is associated with autoimmune inflammatory diseases. In this application will test the central hypothesis that cigarette smoke induced suppression of C1q coordinates the dysregulated innate and acquired immune responses that drive emphysema. The premise of our studies is based on our preliminary data that C1q promotes anti-inflammatory T regulatory cells (Tregs) development and C1q-/- mice show exaggerated lung inflammation in response to chronic smoke. Collectively, our findings point to an immune modulatory role for C1q in emphysema; the significance of our proposal includes understanding mechanism that drive smoke-induced lung inflammation that could provide novel complement-based therapeutics to treat emphysema. Our three Aims are: 1) Determine the anti- inflammatory role of C1q in smoke induced lung inflammation and emphysema. Hypothesis: Cigarette smoke suppresses C1q in lung mDCs and/or alveolar macrophages thereby inhibiting Treg differentiation and/or function, and inducing autoreactive T cells. 2) Determine the molecular mechanisms responsible for cigarette smoke-mediated loss of C1q, and reduction of immune tolerance. Hypothesis: Cigarette smoke- induced activation of IL-1?? IL-6, and/or C3a, suppress C1q in lung mDCs and/or alveolar macrophages and reduce lung Tregs. 3) Determine the signaling pathways in T cells responsible for C1q-mediated enhancement of Treg differentiation. Hypotheses: C1q-mediated signaling pathways in T cells are critical for maintenance of immune tolerance.